tbuckley/cabot-search huggingface dataset:
OTHR-13. IDENTIFYING INDIVIDUALS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS AT RISK FOR HEREDITARY CANCER SYNDROMES USING A STATEWIDE CANCER REGISTRY
Authors: Nicholas Whipple, David Zhe Yu, Samuel Cheshier, Joshua Schiffman, Karen Curtin, Wendy Kohlmann
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Central Nervous System (CNS) tumors are associated with hereditary cancer syndromes (HCS), especially among pediatric and AYA populations. Using population-based resources, we evaluated the proportion of patients meeting HCS testing criteria. METHODS Cases of CNS tumors diagnosed in individuals ages 0-39 were identified through the Utah Cancer Registry. Using the Utah Population Database, cases were linked to cancer family history and, when available, to HCS genetic data. A genetic counselor and pediatric neuro-oncologist reviewed family pedigrees containing ≥2 CNS tumors. RESULTS We identified 347 CNS tumors in 320 individuals, from 161 families (FSIR P&amp;lt;0.05). The most common tumors were: astrocytoma (n=93), pituitary (n=38), glioma (n=34, 4 optic nerve), glioblastoma (n=32), meningioma (n=31), oligodendroglioma (n=24), and medulloblastoma (n=20). Sixteen individuals had multiple cancers: 9 had ≥ 2 CNS tumors, 7 had CNS and non-CNS tumors. Of those with multiple tumors, 3 met criteria for NF2, 1 for NF1, and 1 for Chompret. 213 individuals (67%) met criteria for HCS testing based on their personal cancer history. Criteria met included glial tumor (&amp;lt; age 40) (n=163), NF2 (n=14), NF1 (n=12), rhabdoid tumor predisposition (n=10), Chompret (n=7), VHL (n=3), medulloblastoma—SHH (n=3), DICER1 (n=1). Germline data were available for 23 individuals, and 14 had a germline mutation (Li Fraumeni Syndrome=8, VHL=3, APC=1, DICER1=1). An additional 12 people met Chompret criteria based on their CNS tumor plus family history. Of these 4 had germline testing, of which 3 had LFS. CONCLUSIONS In our cohort, 70% of individuals met criteria for HCS testing. However, this may be an underestimate because many syndromes associated with CNS tumors also predispose to non-CNS tumors, which were not included in the initial query. Research on the actual prevalence of HCS in individuals with CNS tumors requires germline data in a queryable form in the medical record.
HGG-07. OVEREXPRESSION OF A PLAG-FAMILY TRANSCRIPTION FACTOR DURING MURINE BRAIN DEVELOPMENT CAUSES BRAIN TUMOR FORMATION
Authors: Jan Vaillant, Andrea Wittmann, Michaela-Kristina Keck, Jacob S Rozowsky, Mariella G Filbin, Stefan M Pfister, David T W Jones, Lena M Kutscher
Journal: Neuro-Oncology (2023)

Abstract Pediatric-type gliomas are the most common type of central nervous system tumors in children. They are highly diverse regarding their molecular entities and clinical associations, and they differ from their adult counterparts. A subset of pediatric-type high grade gliomas, including H3K27M mutated diffuse midline glioma, overexpresses the developmentally regulated transcription factor gene PLAG1. Two novel tumor types displaying amplifications or fusions with the related PLAGL1 and PLAGL2 genes have also recently been described (PMIDs 36437415, 34355256). How PLAG-family dysregulation drives tumor formation is currently unknown, however. We generated a novel mouse model that overexpresses hPLAG1 during brain development using a Cre-LoxP approach. Mice that overexpress hPLAG1 together with loss of trp53 in the Nestin-Cre lineage develop brain tumors by 3 months of age with 100 % penetrance. Intriguingly, tumors develop in different brain regions, with hotspots in the thalamus or inferior hypothalamus, the latter likely emerging from the brainstem. All mouse brains contain regions in the brainstem, thalamus and the prefrontal cortex with diffuse patterns of PLAG1+; KI67+ proliferating single cells. Using bulk-RNA sequencing, we identified several genes involved in embryonic brain development, which are still active in the tumors of adult mice. We hypothesize that continued overexpression of PLAG1 locks cells in an aberrant developmental state, making them susceptible for further oncogenic hits and ultimately leading to pediatric glioma formation. We are currently using single-nucleus RNA-seq to determine the developmental trajectories of single tumor cells to identify putative cells-of-origin and primary developmental pathways. Our work will elucidate the consequences of PLAG1 overexpression in pediatric brain tumors and its contribution to tumorigenesis. In the future, we hope to identify genetic dependencies of PLAG1 to generate novel treatment options.
EPEN-13. PATTERN OF RELAPSE IN POSTERIOR FOSSA EPENDYMOMA GROUP A
Authors: Inci Yaman Bajin, Michal Zapotocky, Ute Bartels, Uri Tabori, Annie Huang, Derek Tsang, Normand Laperierre, Peter Dirks, Suzanne Laughlin, Eric Bouffet, Vijay Ramaswamy
Journal: Neuro-Oncology (2023)

Abstract PURPOSE/OBJECTIVE Posterior fossa ependymoma group A (PF-EPN-A) is a poor prognostic ependymoma subgroup, predominantly seen in infants and young children. Among all ependymomas, most of the recurrences are seen in patients with the PF-EPN-A subgroup. Despite advances in neurosurgery and postoperative adjuvant therapy, management of these tumors remains challenging, and recurrence occurs in over 50% of cases. In this study, we aimed to evaluate the pattern of relapse in PF-EPN-A. MATERIALS AND METHODS The clinical features, treatment strategies and relapse patterns of patients diagnosed and treated with PF-EPN-A at the Hospital for Sick Children, Toronto have been evaluated retrospectively. RESULTS Seventy-five patients were diagnosed with PF-EPN-A at the Hospital for Sick Children, Toronto from 01 June 1996 to 01 June 2022. All patients were treated with surgery +/- focal radiation +/- chemotherapy after diagnosis. Out of 75 patients, 38 (50.6%) had recurrent disease. Twenty-three patients (60.5%) had a local relapse while 15 patients (40.5) experienced a distant relapse. Out of 23 patients who had a local relapse, only 8 patients (34%) developed a local relapse after a gross total resection (GTR). Other 15 patients developed a local relapse after either subtotal (STR) or near total resection (nTR). Out of 15 patients who experienced a distant relapse, 10 patients (66%) developed a distant relapse after GTR. Time to relapse was mean 32 months (11-132 months) after GTR and 24 months (1-98 months) after STR /nTR. CONCLUSIONS The modern management approach (more aggressive resection and early conformal radiotherapy) changed the relapse pattern and the classical dogma that “nearly all relapses in ependymoma are local’’ in modern series. This study supported the importance of GTR in the management of PF-EPN-A and also demonstrated that PF-EPN-A tends to recur more on distant sites rather than locally when the initial surgical intervention is a GTR.
HGG-04. INFANTILE HIGH GRADE GLIOMA: HONG KONG EXPERIENCE
Authors: Sarah Sau Ning Lau, Dennis Tak Loi Ku, Pak Yin Anthony Liu
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To review local infantile high-grade glioma (IHG) patients and their outcome. BACKGROUND Infantile high-grade glioma is diagnosed in patients less than 12 months of age. Studies have shown that it displays a more stable genome, and are usually single mutation driven. The most identifiable mutations are receptor tyrosine kinase (RTK) fusion, such as NTRK family, ROS1, ALK and MET. The current principal treatment remains to be surgery, but it is challenging for a complete resection due to hemispheric involvement. Chemotherapeutic drugs for IHG are still under debate, with targeted therapy showing efficacy in promoting tumour shrinkage. Despite being a challenging CNS tumour, the overall survival of IHG is superior to other paediatric high-grade gliomas. Result: We identified 7 IHG patients in our local data. Mean age of diagnosis was 3 months. There were 4 males and 3 females. Six patients had histological diagnosis of glioblastoma and 1 patient had diagnosis of anaplastic astrocytoma. One patient had her tumour located in infratentorial region. Three patients had multilobar involvement. NTRK fusion was found in 4 patients (NTRK fusion, ETV6-NTRK3 fusion and TPR-NTRK1 fusion). ALK fusion was found in 1 patient (HMBOX1-ALK). All patients underwent chemotherapy, with four patients switched to NTRK inhibitor afterwards. Surgery was performed at various time points for these patients. One patient passed away at 22 months of age at submission of this abstract. CONCLUSION A local review gives us more insight into the updated diagnosis, management and outcome of infantile patients diagnosed with high-grade glioma. Infantile high-grade glioma should be regarded as a unique tumour entity and a multidisciplinary approach is paramount in improving survival for this group of patients.
ATRT-01. PARP INHIBITION AS A THERAPEUTIC TARGET IN ATRT
Authors: Irina Alimova, Gillian Mardok, Angela Pierce, Dong Wang, Krishna Madhavan, Breauna Brunt, Rajeev Vibhakar
Journal: Neuro-Oncology (2023)

Abstract Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with poor survival. The available treatments rely on toxic chemotherapy and radiotherapy, which alone can cause poor outcomes for young patients. Poly (ADP-ribose) polymerases (PARP), multifunctional enzymes which play an important role in DNA damage repair and genome stability have emerged as a new target in cancer therapy. An FDA approved drug screen revealed that Rucaparib, a PARP inhibitor, is important for ATRT cell growth.In this study we investigated the effect of Rucaparib treatment in ATRT. Using MTS and colony formation assays we found that Rucaparib treatment decreased ATRT cell growth and inhibited clonogenic potential of ATRT cells. Flow cytometry and Western blot analysis showed that Rucaparib treatment led to cell cycle arrest and apoptosis. Moreover, Rucaparib treatment led to DNA damage accumulation as seen by increased expression of yH2AX by immunofluorescence. In vivo, Rucaparib treatment significantly decreased tumor growth and prolonged survival in orthotopic mouse models. Furthermore, Immunohistochemistry revealed an increased number of P53 and Caspase3positive cells in the Rucaparib treatment group, confirming the induction of apoptosis in vivo. Furthermore, Rucaparib pretreatment sensitizes ATRT cells to radiation and significantly increased survival of xenograft-bearing mice. Thus, we demonstrated that Rucaparib has potential to be a new therapeutic strategy for ATRT as shown by its ability to decrease ATRT tumor growth both in vitro and in vivo.
An iPSC-derived exosome-pulsed dendritic cell vaccine boosts antitumor immunity in melanoma
Authors: Ronghao Wang, Tianchuan Zhu, Bingzong Hou, Xi Huang
Journal: Molecular Therapy (2023)

Induced pluripotent stem cells (iPSCs) express a broad spectrum of tumor-associated antigens and exert prophylactic effects on various tumors. However, some problems remain, such as potential tumorigenicity, challenges in transport to the lymph nodes and spleen, and limited antitumor effects. Thus, designing a safe and effective iPSC-based tumor vaccine is necessary. We prepared iPSC-derived exosomes and incubated them with DCs (dendritic cells) for pulsing to explore their antitumor effects in murine melanoma models. The antitumor immune response induced by the DC vaccine pulsed with iPSC exosomes (DC + EXO) was assessed in vitro and in vivo. After DC + EXO vaccination, extracted spleen T cells effectively killed a variety of tumor cells (melanoma, lung cancer, breast cancer, and colorectal cancer) in vitro. In addition, DC + EXO vaccination significantly inhibited melanoma growth and lung metastasis in mouse models. Furthermore, DC + EXO vaccination induced long-term T cell responses and prevented melanoma rechallenge. Finally, biocompatibility studies showed that the DC vaccine did not significantly alter the viability of normal cells and mouse viscera. Hence, our research may provide a prospective strategy of a safe and effective iPSC-based tumor vaccine for clinical use.
OUTC-04. SUBSEQUENT CNS MALIGNANCY AMONG SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)
Authors: Robert Galvin, Yan Chen, Yan Yuan, Tabitha Cooney, Rebecca Howell, Susan Smith, Michael Arnold, Miriam Conces, Wendy Leisenring, Leslie Robison, Gregory Armstrong, Joseph Neglia, Lucie Turcotte
Journal: Neuro-Oncology (2023)

Abstract Subsequent malignant neoplasms (SMNs) of the central nervous system (CNS) following childhood cancer are a frequently fatal late effect of cancer therapy. We used the CCSS (5-year childhood cancer survivors, diagnosed 1970-1999) to assess whether temporal changes in therapy have reduced CNS SMN risk. Twenty-year cumulative incidence rates (95% confidence interval) were estimated, and standardized incidence ratios (SIR, 95% CI) were calculated comparing observed to expected rates from SEER. Multivariable models assessed demographic and treatment-related risk factors for CNS SMN. Among survivors diagnosed between 1970-1979 (N=6223), 1980-1989 (N=9680), and 1990–1999 (N=8999) with median follow-up of 40.5, 32.2, and 22.6 years, respectively, 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas. Malignant gliomas (N=131) were the most common SMNs. Cranial radiotherapy (CRT) exposure decreased by treatment decade, with the proportion of survivors receiving no CRT increasing from 23.0% (1970s), to 45.7% (1980s), and 66% (1990s). Decreases in &amp;gt;0–10Gy exposure (39.0% to 14.1%) and 20.1–30Gy (19.2% to 2.4%) were observed while those receiving &amp;gt;30Gy CRT has not substantially changed (12%, 11.1%, and 8.8%, respectively). Twenty-year cumulative incidence and SIR for development of SMN were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant differences between treatment eras, including when stratified by attained age. Multivariate analysis showed increased risk for all CRT dose levels &amp;gt;10Gy and for primary diagnoses of medulloblastoma/PNET (HR 3.6, 2.0-6.6) and astrocytoma (HR 2.4, 1.4-3.9). Three-year cumulative incidences of death after SMN, by treatment decade, were 70%, 73%, and 69%, respectively. In conclusion, CNS SMN incidence has not decreased despite fewer survivors being treated with CRT, and CNS SMNs remain a significant source of mortality for affected patients.
IMMU-04. TARGETING ALTERNATIVE SPLICING VARIANTS TO STIMULATE ANTI-TUMOR IMMUNITY IN A NOVEL SYNGENEIC MOUSE MODEL OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Geoffrey Owens, Yang Pan, Janet Treger, Erick Contreras, Horacio Soto, Amber Armellini, Brian Na, Linda Liau, Robert Prins, Yi Xing, Anthony Wang
Journal: Neuro-Oncology (2023)

Abstract Juvenile presentation of HGG has been shown to frequently involve somatic mutations of the H3-3A gene, which encodes a histone H3 variant. To address the paucity of identified TSAs in DHG, we utilized a novel computational platform, Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS). The IRIS pipeline is designed to leverage large-scale cancer and normal transcriptomic data to identify peptide sequences that result from alternative splicing events that are highly enriched in cancer cells, and are predicted to bind the HLA class I alleles carried by the individual patient. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant, we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens. We used the RCAS/tv-A system to target the expression of H3/G34R and PDGF-B and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. Implementing IRIS, we identified nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two H3/G34R patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele.
BIOL-18. NEWLY DEVELOPED REPLICATION REPAIR DEFICIENT (RRD) MOUSE MODELS PROVIDE INSIGHTS INTO MEDULLOBLASTOMA/GLIOMAGENESIS AND RESPONSE TO IMMUNOTHERAPY
Authors: Zoya Aamir, Melissa Galati, Emma Gattoni, Owen Crump, Nuno M Nunes, Anirban Das, Nicholas R Fernandez, Angel K Q Wong, Jerome Fortin, Lucie Stengs, Vanessa Bianchi, Melissa Edwards, Logine Negm, Jiil Chung, David Malkin, Sean Egan, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract Replication Repair Deficiency (RRD), caused by germline monoallelic (Lynch Syndrome) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes, is present in 5-10% of glioblastomas in children, adolescents, and young adults. RRD glioblastomas are chemoradiation-resistant, but respond favorably to immune checkpoint inhibition (ICI). Representative immunocompetent animal models are urgently needed for 3 recently identified subgroups based on specific somatically-acquired mutations, survival, and immunotherapy response (RRD1: MMRD with POLE mutations, RRD2: MMRD associated with TP53 mutations, and RRD3: MMRD harboring IDH1 mutations). Using germline mutations and brain-specific Cre-drivers, we genetically engineered mouse models that recapitulate each human RRD-subgroup. RRD1 (Nestin- and Olig2-Cre+/ Msh2LoxP/LoxP/PoleS459F/+ and LSL-PoleP286R/+): CMMRD-like Nestin-Cre-driven mice develop posterior-fossa glioma-like or medulloblastoma (MB)-like tumors at ~2.7 months. Olig2-Cre-driven mice display hemispheric gliomas at ~10 months, suggesting distinct cell-of-origin. RRD2 (Nestin-Cre+/Trp53LoxP/LoxP and Msh2LoxP/LoxP or Mlh1-/-): CMMRD-like tumors develop in heterogenous locations at ~4.5 months (p&amp;lt;0.0001), classifying primarily as MB-like in hindbrain, and glioma-like in other brain regions. Strikingly, germline Mlh1 tumors occur earlier than Nestin-Cre-driven RRD2 tumors, indicating early developmental mutation accumulation in CMMRD-patients. Lynch-like RRD1/2 mice succumb exclusively to gliomas &amp;gt;13 months (p&amp;lt;0.0001). RRD3 (Olig2-Cre+/Msh2LoxP/LoxP/Trp53LoxP/LoxP/LSL-Idh1R132H/+): brain tumors occur later and are hemispheric. These observations recapitulate human data, where CMMRD-patients develop glioblastoma/MB earlier than Lynch-patients (8.6 vs. 14-years; p&amp;lt;0.0001), and posterior-fossa glioblastoma/MB presents earlier than hemispheric gliomas (p=0.04). Additionally, tumor onset and location vary (RRD1: 7.6-years, RRD2: 8.3-years, hemispheric/posterior-fossa; RRD3: 12-years, hemispheric; p=0.005). In both mice and humans, RRD1 exhibits ultra-hypermutation, high immune infiltration, and response to ICI, whereas RRD2 harbors lower mutational burden, are immune-cold, and ICI-monotherapy resistant. Temporal dynamics of RRD tumor development is currently being tracked by serial MRI to define biologically relevant time points. Our models accurately mimic the human condition and provide unique insights into RRD tumorigenesis, allowing optimization of subgroup-tailored therapeutic approaches.
METB-04. THE MOLECULAR CHARACTERIZATION INITIATIVE (MCI): A CLINICAL AND GENOMIC RESOURCE FOR THE PEDIATRIC BRAIN TUMOR COMMUNITY
Authors: Sarah Leary, Diana Thomas, Catherine Cottrell, Yu Wang, Erin Rudzinski, Nilsa Ramirez, Douglas Hawkins, Maryam Fouladi, Elaine Mardis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Molecular Characterization Initiative (MCI) sponsored by the National Cancer Institute (NCI) as part of the Childhood Cancer Data Initiative provides free clinical molecular testing with return of results to treating institutions. METHODS The MCI was activated as an optional sub-study of the COG Project:EveryChild registry, eligibility screening, biology and outcome study. Eligibility for subjects with central nervous system (CNS) tumors included newly diagnosed benign and malignant tumors in subjects &amp;lt; 25 years. Clinical testing included exome sequencing of paired tumor/normal; DNA methylation array for CNS tumor classification; and targeted RNA sequencing for fusion detection. Required specimens were tumor (snap frozen, FFPE block or slides) and whole blood. Quality control confirming presence and percentage of tumor was confirmed by central pathologist. Minimum nucleic acid yield included 300ng DNA (frozen, 700ng from fixed tissue) and 500ng RNA. RESULTS In the first 10 months since activation 3/21/2022, 867 CNS subjects from 149 COG institutions have enrolled in the MCI, of which 675 (78% of enrolled) have submitted both required tumor and blood specimens. Adequate nucleic acids were extracted from 592 specimens (88% of submitted). For subjects with adequate nucleic acids, DNA exome and methylation classification results were returned for 99%; RNA fusion analysis was returned for 93%. Median time to return of results was 19 days from receipt of tumor specimens. Only 16% of CNS subjects were also participating in screening for COG therapeutic studies, including medulloblastoma (7%), low-grade glioma (6%) and high-grade glioma (4%). Genomic and annotated clinical data are available within the NIH-sponsored repository, dbGAP, through controlled access request by academic investigators. CONCLUSIONS The MCI represents an unprecedented resource of genomic and clinical data that is readily available to improve clinical diagnosis and support pediatric brain tumor research.